Delta opioid receptors (DORs) have been considered as a potential target to relieve pain as well as treat depression and anxiety disorders, and are known to modulate other physiological responses, including ethanol and food consumption. A small number of DOR selective drugs are in clinical trials, but no DOR selective drugs have been approved by the Federal Drug Administration and some candidates have failed in phase II clinical trials, highlighting current difficulties producing effective delta opioid based therapies. Recent studies have provided new insights into the pharmacology of the DOR, which is often complex and at times paradoxical. This review will discuss the existing literature focusing on four aspects: 1) Two DOR subtypes have been postulated based on differences in pharmacological effects of existing DOR-selective ligands 2) DORs are expressed ubiquitously throughout the body and central nervous system and are, thus, positioned to play a role in a multitude of diseases. 3) DOR expression is often dynamic, with many reports of increased expression during exposure to chronic stimuli, such as stress, inflammation, neuropathy, morphine, or changes in endogenous opioid tone. 4) A large structural variety in DOR ligands implies potential different mechanisms of activating the receptor. These combined features of DOR pharmacology illustrate the potential benefit of designing tailored or biased DOR ligands.

Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines. The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets. However, current in vitro assays are ill equipped to detect heteromer-selective compounds. We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable. Here we show that this assay can demonstrate heteromer-selective G-protein bias as well as measure transinhibition. Using this assay, we reveal that the d-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against d-opioid receptor homomers than d/m-opioid receptor heteromers (pEC 50 5 6.7 6 0.1 versus 5.8 6 0.2). The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents.

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